A proton-inhibited DEG/ENaC ion channel maintains neuronal ionstasis and promotes neuronal survival under stress

Dionysia Petratou; Martha Gjikolaj; Eva Kaulich; William Schafer; Nektarios Tavernarakis

doi:10.1016/j.isci.2023.107117

A proton-inhibited DEG/ENaC ion channel maintains neuronal ionstasis and promotes neuronal survival under stress

iScience. 2023 Jun 14;26(7):107117. doi: 10.1016/j.isci.2023.107117. eCollection 2023 Jul 21.

Authors

Dionysia Petratou^{1

2}, Martha Gjikolaj^{1

2}, Eva Kaulich³, William Schafer³, Nektarios Tavernarakis^{1

2}

Affiliations

¹ Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Heraklion, 70013 Crete, Greece.
² Department of Basic Sciences, Medical School, University of Crete, Heraklion, 71003 Crete, Greece.
³ Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, CB2 0QH Cambridge, UK.

Abstract

The nervous system participates in the initiation and modulation of systemic stress. Ionstasis is of utmost importance for neuronal function. Imbalance in neuronal sodium homeostasis is associated with pathologies of the nervous system. However, the effects of stress on neuronal Na⁺ homeostasis, excitability, and survival remain unclear. We report that the DEG/ENaC family member DEL-4 assembles into a proton-inactivated sodium channel. DEL-4 operates at the neuronal membrane and synapse to modulate Caenorhabditis elegans locomotion. Heat stress and starvation alter DEL-4 expression, which in turn alters the expression and activity of key stress-response transcription factors and triggers appropriate motor adaptations. Similar to heat stress and starvation, DEL-4 deficiency causes hyperpolarization of dopaminergic neurons and affects neurotransmission. Using humanized models of neurodegenerative diseases in C. elegans, we showed that DEL-4 promotes neuronal survival. Our findings provide insights into the molecular mechanisms by which sodium channels promote neuronal function and adaptation under stress.

Keywords: Neurogenetics; Neurology.